Characterization of the zebrafish as a model of ATP-sensitive potassium channel hyperinsulinism.

INTRODUCTION: Congenital hyperinsulinism (HI) is the leading cause of persistent hypoglycemia in infants. Current models to study the most common and severe form of HI resulting from inactivating mutations in the ATP-sensitive potassium channel (KATP) are limited to primary islets from patients and the Sur1 -/- mouse model. Zebrafish exhibit potential as a novel KATPHI model since they express canonical insulin secretion pathway genes and those with identified causative HI mutations. Moreover, zebrafish larvae transparency provides a unique opportunity for in vivo visualization of pancreatic islets. RESEARCH DESIGN AND METHODS: We evaluated zebrafish as a model for KATPHI using a genetically encoded Ca2+ sensor (ins:gCaMP6s) expressed under control of the insulin promoter in beta cells of an abcc8 -/- zebrafish line. RESULTS: We observed significantly higher islet cytosolic Ca2+ in vivo in abcc8 -/- compared with abcc8 +/+ zebrafish larvae. Additionally, abcc8 -/- larval zebrafish had significantly lower whole body glucose and higher whole body insulin levels compared with abcc8 +/+ controls. However, adult abcc8 -/- zebrafish do not show differences in plasma glucose, plasma insulin, or glucose tolerance when compared with abcc8 +/+ zebrafish. CONCLUSIONS: Our results identify that zebrafish larvae, but not adult fish, are a demonstrable novel model for advancement of HI research.

Novel Use of Dasiglucagon, a Soluble Glucagon Analog, for the Treatment of Hyperinsulinemic Hypoglycemia Secondary to Suspected Insulinoma: A Case Report.

INTRODUCTION: Hyperinsulinemic hypoglycemia is the most common cause of persistent hypoglycemia in children and adults. In adolescents and adults, hyperinsulinemic hypoglycemia is most frequently caused by an insulin-producing tumor. CASE PRESENTATION: A 17-year-old, previously healthy male presented with recurrent and severe episodes of hypoglycemia. Diagnostic evaluation was consistent with hyperinsulinemic hypoglycemia, and an insulinoma was suspected. Multiple imaging studies and surgical exploration failed to identify a lesion. Over the course of months, the patient was found to be refractory to conventional medical interventions. CONCLUSION: Upon approval from the US Food and Drug Administration and the Institutional Review Board, the patient was treated with dasiglucagon, a novel soluble glucagon analog, under a single-patient Investigational New Drug. The patient has tolerated the medication and has been able to achieve appropriate glycemic control.

Dasiglucagon for the Treatment of Congenital Hyperinsulinism: A Randomized Phase 3 Trial in Infants and Children.

CONTEXT: Congenital hyperinsulinism (CHI) is characterized by dysregulated insulin secretion causing hypoglycemia and consequent brain damage. Dasiglucagon is a glucagon analogue under investigation to treat CHI. OBJECTIVE: To evaluate the efficacy and safety of dasiglucagon delivered via continuous subcutaneous infusion to children with CHI and persistent hypoglycemia as add-on to standard of care (SoC). METHODS: In this open-label trial, patients were randomized 1:1 to SoC or SoC + dasiglucagon (10-70 µg/h) for 4 weeks. In the following 4 weeks, all patients received dasiglucagon + SoC. Hypoglycemia was assessed by self-monitored plasma glucose (SMPG) and blinded continuous glucose monitoring (CGM). Primary endpoint was average number of SMPG-detected hypoglycemia episodes/week (SMPG <3.9 mmol/L) during Weeks 2 to 4. RESULTS: Thirty-two patients (0.6-10.9 years) were randomly assigned to dasiglucagon + SoC (n = 16) or SoC (n = 16). The rate of SMPG-detected hypoglycemia decreased from baseline in both groups, but with no statistically significant difference during Weeks 2 to 4 (event rate ratio: 0.85 [0.54; 1.36], P = .5028). However, dasiglucagon administration resulted in a 43% reduction in CGM-detected hypoglycemia (<3.9 mmol/L) vs SoC alone during Weeks 2 to 4 (post hoc analysis; event rate ratio: 0.57 [0.39; 0.83], P = .0029). Dasiglucagon enabled reductions (of 37% to 61%) in all other measures of hypoglycemia assessed by CGM vs SoC alone including extent and percent time in hypoglycemia (post hoc analyses). Dasiglucagon appeared safe and well tolerated. Skin and gastrointestinal events were more frequent with dasiglucagon + SoC than SoC only. CONCLUSION: Clinically meaningful reductions in all CGM-recorded measures of hypoglycemia support using dasiglucagon as a potential treatment for CHI.

Phenotypic Characterization of Congenital Hyperinsulinism Due to Novel Activating Glucokinase Mutations.

The importance of glucokinase (GK) in the regulation of insulin secretion has been highlighted by the phenotypes of individuals with activating and inactivating mutations in the glucokinase gene (GCK). Here we report 10 individuals with congenital hyperinsulinism (HI) caused by eight unique activating mutations of GCK. Six are novel and located near previously identified activating mutations sites. The first recognized episode of hypoglycemia in these patients occurred between birth and 24 years, and the severity of the phenotype was also variable. Mutant enzymes were expressed and purified for enzyme kinetics in vitro. Mutant enzymes had low glucose half-saturation concentration values and an increased enzyme activity index compared with wild-type GK. We performed functional evaluation of islets from the pancreata of three children with GCK-HI who required pancreatectomy. Basal insulin secretion in perifused GCK-HI islets was normal, and the response to glyburide was preserved. However, the threshold for glucose-stimulated insulin secretion in perifused glucokinase hyperinsulinism (GCK-HI) islets was decreased, and glucagon secretion was greatly suppressed. Our evaluation of novel GCK disease-associated mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. ARTICLE HIGHLIGHTS: Our evaluation of six novel and two previously published activating GCK mutations revealed that the detrimental effects of these mutations on glucose homeostasis can be attributed not only to a lowering of the glucose threshold of insulin secretion but also to a decreased counterregulatory glucagon secretory response. These studies provide insights into the pathophysiology of GCK-hyperinsulinism and the dual role of glucokinase in ß-cells and α-cells to regulate glucose homeostasis.

Optimization of a Glucagon-Like Peptide 1 Receptor Antagonist Antibody for Treatment of Hyperinsulinism.

Congenital hyperinsulinism (HI) is a genetic disorder in which pancreatic ß-cell insulin secretion is excessive and results in hypoglycemia that, without treatment, can cause brain damage or death. Most patients with loss-of-function mutations in ABCC8 and KCNJ11, the genes encoding the ß-cell ATP-sensitive potassium channel (KATP), are unresponsive to diazoxide, the only U.S. Food and Drug Administration-approved medical therapy and require pancreatectomy. The glucagon-like peptide 1 receptor (GLP-1R) antagonist exendin-(9-39) is an effective therapeutic agent that inhibits insulin secretion in both HI and acquired hyperinsulinism. Previously, we identified a highly potent antagonist antibody, TB-001-003, which was derived from our synthetic antibody libraries that were designed to target G protein-coupled receptors. Here, we designed a combinatorial variant antibody library to optimize the activity of TB-001-003 against GLP-1R and performed phage display on cells overexpressing GLP-1R. One antagonist, TB-222-023, is more potent than exendin-(9-39), also known as avexitide. TB-222-023 effectively decreased insulin secretion in primary isolated pancreatic islets from a mouse model of hyperinsulinism, Sur1-/- mice, and in islets from an infant with HI, and increased plasma glucose levels and decreased the insulin to glucose ratio in Sur1-/- mice. These findings demonstrate that targeting GLP-1R with an antibody antagonist is an effective and innovative strategy for treatment of hyperinsulinism. ARTICLE HIGHLIGHTS: Patients with the most common and severe form of diazoxide-unresponsive congenital hyperinsulinism (HI) require a pancreatectomy. Other second-line therapies are limited in their use because of severe side effects and short half-lives. Therefore, there is a critical need for better therapies. Studies with the glucagon-like peptide 1 receptor (GLP-1R) antagonist, avexitide (exendin-(9-39)), have demonstrated that GLP-1R antagonism is effective at lowering insulin secretion and increasing plasma glucose levels. We have optimized a GLP-1R antagonist antibody with more potent blocking of GLP-1R than avexitide. This antibody therapy is a potential novel and effective treatment for HI.

A selective nonpeptide somatostatin receptor 5 agonist effectively decreases insulin secretion in hyperinsulinism.

Congenital hyperinsulinism (HI), a beta cell disorder most commonly caused by inactivating mutations of beta cell KATP channels, results in dysregulated insulin secretion and persistent hypoglycemia. Children with KATP-HI are unresponsive to diazoxide, the only FDA-approved drug for HI, and utility of octreotide, the second-line therapy, is limited because of poor efficacy, desensitization, and somatostatin receptor type 2 (SST2)-mediated side effects. Selective targeting of SST5, an SST receptor associated with potent insulin secretion suppression, presents a new avenue for HI therapy. Here, we determined that CRN02481, a highly selective nonpeptide SST5 agonist, significantly decreased basal and amino acid-stimulated insulin secretion in both Sur1-/- (a model for KATP-HI) and wild-type mouse islets. Oral administration of CRN02481 significantly increased fasting glucose and prevented fasting hypoglycemia compared to vehicle in Sur1-/- mice. During a glucose tolerance test, CRN02481 significantly increased glucose excursion in both WT and Sur1-/- mice compared to the control. CRN02481 also reduced glucose- and tolbutamide-stimulated insulin secretion from healthy, control human islets similar to the effects observed with SS14 and peptide somatostatin analogs. Moreover, CRN02481 significantly decreased glucose- and amino acid-stimulated insulin secretion in islets from two infants with KATP-HI and one with Beckwith-Weideman Syndrome-HI. Taken together, these data demonstrate that a potent and selective SST5 agonist effectively prevents fasting hypoglycemia and suppresses insulin secretion not only in a KATP-HI mouse model but also in healthy human islets and islets from HI patients.

Bridging the gaps: recent advances in diagnosis, care, and outcomes in congenital hyperinsulinism.

PURPOSE OF REVIEW: To highlight advances in congenital hyperinsulinism (HI), including newly described molecular mechanisms of disease, novel therapeutic interventions, and improved understanding of long-term outcomes. RECENT FINDINGS: Important advances have been made elucidating the molecular mechanisms responsible for HI. Non-coding variants in HK1 have been found to cause aberrant hexokinase expression. Inactivating mutations in SLC25A36 have been identified in children with features of the hyperinsulinism hyperammonemia syndrome. Low-level mosaic mutations in known HI genes have been detected in cases of 'genetic testing negative' HI. Identification and localization of focal HI lesions remains a priority, since focal HI can be cured with surgery. Use of 68 Ga-NODAGA-exendin-4 PET has been proposed to localize focal lesions. Additional studies are needed before this technique replaces 18 F-DOPA PET as standard of care. Treatment options for children with diffuse HI remain limited. The long-acting somatostatin analog, lanreotide, was shown to significantly improve glycemic control in a large series of children with HI. New therapies are under development, with promising preliminary results. Long-term quality of life and neurodevelopmental outcomes remain suboptimal. SUMMARY: Advanced genetic and epigenomic analytic techniques have uncovered novel molecular mechanisms of HI. Development of new drugs holds promise to improve long-term outcomes for individuals with HI.

Congenital Hyperinsulinism: An Historical Perspective.

Congenital hyperinsulinism is the most common cause of persistent hypoglycemia in neonates, infants, and children. Since the first case descriptions in the 1950s, the field has advanced significantly. It was the development of the insulin radioimmunoassay by Yalow and Berson a decade later that made it possible to demonstrate that this form of persistent hypoglycemia was caused by insulin, and a few years later, Drash described the successful treatment of children with hyperinsulinism with the antihypertensive diazoxide, which until today remains the only approved treatment for hyperinsulinism. In the mid 1970s, Baker and Stanley described that hyperinsulinism can be recognized by inappropriate responses of metabolic fuels and hormones during the course of a provocative fasting challenge. Later, advances in molecular genetics led to the discovery of the different genetic subtypes of hyperinsulinism. One of the most impactful discoveries in the field was the recognition of the focal form of hyperinsulinism and the development of 18F-DOPA PET for the localization of focal lesions before surgery which has resulted in the possibility of cure for children with focal disease. However, treatment options for children with nonfocal diazoxide-unresponsive hyperinsulinism have continued to be limited. New drug development programs for hyperinsulinism promise to change this in the next few years. Unfortunately, despite all these advances, children with hyperinsulinism around the world continue to experience neurological sequelae at high rates, highlighting the importance of early diagnosis and effective treatment.

Mosaic GLUD1 Mutations Associated with Hyperinsulinism Hyperammonemia Syndrome.

INTRODUCTION: The hyperinsulinemia-hyperammonemia syndrome (HIHA) is the second most common cause of congenital hyperinsulinism and is caused by activating heterozygous missense mutations in GLUD1. In the majority of HIHA cases, the GLUD1 mutation is found to be de novo. We have identified 3 patients in whom clinical evaluation was suggestive of HIHA but with negative mutation analysis in peripheral blood DNA for GLUD1 as well as other known HI genes. METHODS: We performed next-generation sequencing (NGS) on peripheral blood DNA from two children with clinical features of HIHA in order to look for mosaic mutations in GLUD1. Pancreas tissue was also available in one of these cases for NGS. In addition, NGS was performed on peripheral blood DNA from a woman with a history of HI in infancy whose child had HIHA due to a presumed de novo GLUD1 mutation. RESULTS: Mosaic GLUD1 mutations were identified in these 3 cases at percent mosaicism ranging from 2.7% to 10.4% in peripheral blood. In one case with pancreas tissue available, the mosaic GLUD1 mutation was present at 17.9% and 28.9% in different sections of the pancreas. Two unique GLUD1 mutations were identified in these cases, both of which have been previously reported (c.1493c>t/p.Ser445Leu and c.820c>t/p.Arg221Cys). CONCLUSION: The results suggest that low-level mosaic mutations in known HI genes may be the underlying molecular mechanism in some children with HI who have negative genetic testing in peripheral blood DNA.

Effects of GLP-1 and GIP on Islet Function in Glucose-Intolerant, Pancreatic-Insufficient Cystic Fibrosis.

Impaired insulin and incretin secretion underlie abnormal glucose tolerance (AGT) in pancreatic insufficient cystic fibrosis (PI-CF). Whether the incretin hormones glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP) can enhance pancreatic islet function in cystic fibrosis (CF) is not known. We studied 32 adults with PI-CF and AGT randomized to receive either GLP-1 (n = 16) or GIP (n = 16) during glucose-potentiated arginine (GPA) testing of islet function on two occasions, with either incretin or placebo infused, in a randomized, double-blind, cross-over fashion. Another four adults with PI-CF and normal glucose tolerance (NGT) and four matched control participants without CF underwent similar assessment with GIP. In PI-CF with AGT, GLP-1 substantially augmented second-phase insulin secretion but without effect on the acute insulin response to GPA or the proinsulin secretory ratio (PISR), while GIP infusion did not enhance second-phase or GPA-induced insulin secretion but increased the PISR. GIP also did not enhance second-phase insulin in PI-CF with NGT but did so markedly in control participants without CF controls. These data indicate that GLP-1, but not GIP, augments glucose-dependent insulin secretion in PI-CF, supporting the likelihood that GLP-1 agonists could have therapeutic benefit in this population. Understanding loss of GIP's insulinotropic action in PI-CF may lead to novel insights into diabetes pathogenesis.

Localized islet nuclear enlargement hyperinsulinism (LINE-HI) due to ABCC8 and GCK mosaic mutations.

Objective: Congenital hyperinsulinism (HI) is the most common cause of persistent hypoglycemia in children. In addition to typical focal or diffuse HI, some cases with diazoxide-unresponsive congenital HI have atypical pancreatic histology termed Localized Islet Nuclear Enlargement (LINE) or mosaic HI, characterized by histologic features similar to diffuse HI, but confined to only a region of pancreas. Our objective was to characterize the phenotype and genotype of children with LINE-HI. Design: The phenotype and genotype features of 12 children with pancreatic histology consistent with LINE-HI were examined. Methods: We compiled clinical features of 12 children with LINE-HI and performed next-generation sequencing on specimens of pancreas from eight of these children to look for mosaic mutations in genes known to be associated with diazoxide-unresponsive HI (ABCC8, KCNJ11, and GCK). Results: Children with LINE-HI had lower birth weights and later ages of presentation compared to children with typical focal or diffuse HI. Partial pancreatectomy in LINE-HI cases resulted in euglycemia in 75% of cases; no cases have developed diabetes. Low-level mosaic mutations were identified in the pancreas of six cases with LINE-HI (three in ABCC8, three in GCK). Expression studies confirmed that all novel mutations were pathogenic. Conclusion: These results indicate that post-zygotic low-level mosaic mutations of known HI genes are responsible for some cases of LINE-HI that lack an identifiable germ-line mutation and that partial pancreatectomy may be curative for these cases.

The Use of Lanreotide in the Treatment of Congenital Hyperinsulinism.

CONTEXT: Congenital hyperinsulinism (HI) results in severe, persistent hypoglycemia and is associated with high risk of neurodevelopmental deficits. Sixty percent of HI cases are unresponsive to diazoxide, the only Food and Drug Administration-approved drug. Somatostatin analogs are used off-label as second-line treatment; the long-acting somatostatin analogue, lanreotide, has been used to treat HI over the past decade. Existing reports are limited to small case series. OBJECTIVE: To assess the effectiveness and safety of lanreotide in individuals with HI. DESIGN: Retrospective cohort study of individuals with HI treated with lanreotide between 2015 and 2020. SETTING: The Congenital Hyperinsulinism Center at The Children's Hospital of Philadelphia. PATIENTS: Fifty-four individuals with hyperinsulinism treated with lanreotide. MAIN OUTCOME MEASURES: Fasting duration with plasma glucose > 70 mg/dL; frequency of lanreotide-associated side effects. RESULTS: The median duration of lanreotide therapy was 28.7 (2.8-64.5) months. Thirty-four patients (63%) had HI due to inactivating mutations of the adenosine 5'-triphosphate (ATP) sensitive potassium channel (KATP-HI), and 39% had undergone a pancreatectomy. Of 52 patients receiving other HI therapies, 22 (42%) were able to discontinue other treatments and were managed on lanreotide alone. Fasting duration with plasma glucose > 70 mg/dL was significantly longer during therapy with lanreotide compared to prior to lanreotide initiation (8.6 ±â€…6.5 vs 5.1 ±â€…4.7 hours, P = 0.001). The most common side effects were subcutaneous nodules (26%) and gallstones (11%). CONCLUSIONS: Lanreotide is a well-tolerated treatment for patients with HI. It results in a longer duration of fasting and a simplification of treatment regimens.

Exendin-(9-39) Effects on Glucose and Insulin in Children With Congenital Hyperinsulinism During Fasting and During a Meal and a Protein Challenge.

OBJECTIVE: The aim of this study was to assess whether exendin-(9-39) will increase fasting and postprandial plasma glucose and decrease the incidence of hypoglycemia in children with hyperinsulinism (HI). RESEARCH DESIGN AND METHODS: This was an open-label, four-period crossover study. In periods 1 and 2, the effect of three different dosing regimens of exendin-(9-39) (group 1, 0.28 mg/kg; group 2, 0.44 mg/kg; group 3, 0.6 mg/kg) versus vehicle on fasting glucose was assessed in 16 children with HI. In periods 3 and 4, a subset of eight subjects received either vehicle or exendin-(9-39) (0.6 mg/kg) during a mixed-meal tolerance test (MMTT) and an oral protein tolerance test (OPTT). RESULTS: Treatment group 2 showed 20% (P = 0.037) increase in the area under the curve (AUC) of fasting glucose. A significant increase in AUC of glucose was also observed during the MMTT and OPTT; treatment with exendin-(9-39) resulted in 28% (P ≤ 0.001) and 30% (P = 0.01) increase in AUC of glucose, respectively. Fasting AUC of insulin decreased by 57% (P = 0.009) in group 3. In contrast, AUC of insulin was unchanged during the MMTT and almost twofold higher (P = 0.004) during the OPTT with exendin-(9-39) treatment. In comparison with vehicle, infusion of exendin-(9-39) resulted in significant reduction in likelihood of hypoglycemia in group 2, by 76% (P = 0.009), and in group 3, by 84% (P = 0.014). Administration of exendin-(9-39) during the OPTT resulted in 82% (P = 0.007) reduction in the likelihood of hypoglycemia. CONCLUSIONS: These results support a therapeutic potential of exendin-(9-39) to prevent fasting and protein-induced hypoglycemia in children with HI.

The Role of GLP-1 Signaling in Hypoglycemia due to Hyperinsulinism.

Incretin hormones play an important role in the regulation of glucose homeostasis through their actions on the beta cells and other tissues. Glucagon-like peptide-1 (GLP-1) and glucose dependent insulinotropic polypeptide (GIP) are the two main incretins and are secreted by enteroendocrine L- and K-cells, respectively. New evidence suggests that incretin hormones, particularly GLP-1, play a role in the pathophysiology of hyperinsulinemic hypoglycemia. In individuals with acquired hyperinsulinemic hypoglycemia after gastrointestinal surgery, including Nissen fundoplication and gastric bypass surgery, the incretin response to a meal is markedly increased and antagonism of the GLP-1 receptor prevents the hyperinsulinemic response. In individuals with congenital hyperinsulinism due to inactivating mutations in the genes encoding the beta cell KATP channels, the GLP-1 receptor antagonist, exendin-(9-39), increases fasting plasma glucose and prevents protein-induced hypoglycemia. Studies in human and mouse islets lacking functional KATP channels have demonstrated that the effect on plasma glucose is at least in part mediated by inhibition of insulin secretion resulting from lower cytoplasmic cAMP levels. The understanding of the role of incretin hormones in the pathophysiology of hyperinsulinemic hypoglycemia is important for the exploration of the GLP-1 receptor as a therapeutic target for these conditions. In this article, we will review incretin physiology and evidence supporting a role of the incretin hormones in the pathophysiology of hyperinsulinemic hypoglycemia, as well as results from proof-of concept studies exploring a therapeutic approach targeting the GLP-1 receptor to treat hyperinsulinemic hypoglycemia.

Congenital hyperinsulinism in infancy and childhood: challenges, unmet needs and the perspective of patients and families.

BACKGROUND: Congenital hyperinsulinism (CHI) is the most common cause of persistent hypoglycemia in infants and children, and carries a considerable risk of neurological damage and developmental delays if diagnosis and treatment are delayed. Despite rapid advances in diagnosis and management, long-term developmental outcomes have not significantly improved in the past years. CHI remains a disease that is associated with significant morbidity, and psychosocial and financial burden for affected families, especially concerning the need for constant blood glucose monitoring throughout patients' lives. RESULTS: In this review, we discuss the key clinical challenges and unmet needs, and present insights on patients' and families' perspective on their daily life with CHI. Prevention of neurocognitive impairment and successful management of patients with CHI largely depend on early diagnosis and effective treatment by a multidisciplinary team of specialists with experience in the disease. CONCLUSIONS: To ensure the best outcomes for patients and their families, improvements in effective screening and treatment, and accelerated referral to specialized centers need to be implemented. There is a need to develop a wider range of centers of excellence and networks of specialized care to optimize the best outcomes both for patients and for clinicians. Awareness of the presentation and the risks of CHI has to be raised across all professions involved in the care of newborns and infants. For many patients, the limited treatment options currently available are insufficient to manage the disease effectively, and they are associated with a range of adverse events. New therapies would benefit all patients, even those that are relatively stable on current treatments, by reducing the need for constant blood glucose monitoring and facilitating a personalized approach to treatment.

Congenital hyperinsulinism (CHI) is a rare disease that causes newborn babies and children to have low blood sugar because of the abnormal release of insulin. Insulin is a hormone produced by the pancreas that promotes the transfer of sugar from the blood into the body's cells. In a healthy person, insulin is released only after a meal when the level of blood sugar is high, but infants and children with CHI make insulin even if the blood sugar is low. This can lead to dangerously low blood sugar levels, which can cause brain damage if left untreated. Unfortunately, diagnosis and treatment are often delayed, resulting in avoidable brain damage and developmental delays in these children. CHI is associated with substantial stress and anxiety for the families, especially due to the need for frequent feeding and the fear of low blood sugars added to the constant need to measure blood sugar levels. This article discusses the most important challenges and unmet needs in this rare disease, including the limited treatment options, the side effects of available treatment options and the heavy psychological, social and financial burden on affected families. Effective screening of newborns for CHI needs to be improved, and quick referral to specialized treatment centers is necessary to ensure the best outcomes for patients and families. In addition, awareness of CHI has to be raised in all medical professions caring for newborns and infants, and new medications are urgently needed to ensure the best possible treatment for all patients with CHI.

Congenital hyperinsulinism: localization of a focal lesion with 18F-FDOPA positron emission tomography.

Hyperinsulinemic hypoglycemia of infancy, also known as congenital hyperinsulinism, is a group of disorders characterized by dysregulated insulin release. Neonates with severe, persistent hyperinsulinemic hypoglycemia who are unresponsive to medical therapy require pancreatectomy to prevent brain damage from hypoglycemia. To date, multiple genetic mutations and syndromes and several unique histopathological entities have been identified in children with hyperinsulinism. Histopathology is characterized as diffuse, focal or atypical. Surgical resection of a focal lesion results in a cure in up to 97% of these children. Imaging with 6-fluoro-(18F)-L-3,4-dihydroxyphenylalanine (18F-FDOPA) positron emission tomography (PET) is the test of choice for identifying and localizing a focal lesion and has proved to be an invaluable guide for surgical resection. Genetic evaluation is essential for determining who will benefit from PET imaging. This article provides an approach to determine who should be imaged, how to set up a protocol and how to interpret the imaging findings. The diagnosis and management of this disorder require a multidisciplinary approach to prevent brain damage from hypoglycemia.

Incidence and risk factors for hypoglycemia during maintenance chemotherapy in pediatric acute lymphoblastic leukemia.

BACKGROUND: Fasting hypoglycemia is a recognized occurrence among pediatric patients with acute lymphoblastic leukemia (ALL) during maintenance therapy. Existing publications describing this finding are limited to small studies and case reports. Our objective was to determine the incidence of hypoglycemia during maintenance chemotherapy and to investigate the association of age, as well as other potential risk factors, with this outcome in pediatric patients with ALL. PROCEDURE: This retrospective cohort study included individuals 1 to 21 years of age with ALL treated with antimetabolite-containing maintenance chemotherapy at a large children's hospital between January 2011 and December 2014. The primary endpoint was time to first documented episode of hypoglycemia during maintenance therapy, defined as single measurement of plasma glucose <60 mg/dL. Cox regression was used to evaluate the association with age and identify other potential risk factors. RESULTS: We identified 126 eligible patients, of whom 63% were documented as White, non-Hispanic, 28% as non-White, non-Hispanic, and 9% as Hispanic. Twenty-eight children (22%) had documented hypoglycemia during maintenance therapy. Younger age at the start of maintenance and hepatotoxicity documented during chemotherapy prior to maintenance initiation were associated with hypoglycemia (adjusted HR age = 0.88; 95% CI, 0.78-0.99; adjusted HR prior hepatotoxicity = 3.50; 95% CI, 1.47-8.36). CONCLUSIONS: Nearly one quarter of children in our cohort had hypoglycemia documented during maintenance chemotherapy. Younger age at maintenance initiation and hepatotoxicity during chemotherapy prior to maintenance initiation emerged as risk factors. These findings highlight the importance of counseling about the risk of, and monitoring for, hypoglycemia, particularly in young children.

Effect of Sitagliptin on Islet Function in Pancreatic Insufficient Cystic Fibrosis With Abnormal Glucose Tolerance.

PURPOSE: Impaired incretin secretion may contribute to the defective insulin secretion and abnormal glucose tolerance (AGT) that associate with worse clinical outcomes in pancreatic insufficient cystic fibrosis (PI-CF). The study objective was to test the hypothesis that dipeptidyl peptidase-4 (DPP-4) inhibitor-induced increases in intact incretin hormone [glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)] concentrations augment insulin secretion and glucagon suppression and lower postprandial glycemia in PI-CF with AGT. METHODS: 26 adults from Children's Hospital of Philadelphia and University of Pennsylvania CF Center with PI-CF and AGT [defined by oral glucose tolerance test glucose (mg/dL): early glucose intolerance (1-h ≥ 155 and 2-h < 140), impaired glucose tolerance (2-h ≥ 140 and < 200 mg/dL), or diabetes (2-h ≥ 200)] were randomized to a 6-month double-blind trial of DPP-4 inhibitor sitagliptin 100 mg daily or matched placebo; 24 completed the trial (n = 12 sitagliptin; n = 12 placebo). Main outcome measures were mixed-meal tolerance test (MMTT) responses for intact GLP-1 and GIP, insulin secretory rates (ISRs), glucagon suppression, and glycemia and glucose-potentiated arginine (GPA) test-derived measures of ß- and α-cell function. RESULTS: Following 6-months of sitagliptin vs placebo, MMTT intact GLP-1 and GIP responses increased (P < 0.001), ISR dynamics improved (P < 0.05), and glucagon suppression was modestly enhanced (P < 0.05) while GPA test responses for glucagon were lower. No improvements in glucose tolerance or ß-cell sensitivity to glucose, including for second-phase insulin response, were found. CONCLUSIONS: In glucose intolerant PI-CF, sitagliptin intervention augmented meal-related incretin responses with improved early insulin secretion and glucagon suppression without affecting postprandial glycemia.